ISSN 0006-2979, Biochemistry (Moscow), 2018, Vol. 83, No. 9, pp. 1075-1082. © Pleiades Publishing, Ltd., 2018. Original Russian Text © N. V. Ponomareva, T. V. Andreeva, M. A. Protasova, Yu. V. Filippova, E. P. Kolesnikova, V. F. Fokin, S. N. Illarioshkin, E. I. Rogaev, 2018, published in Biokhimiya, 2018, Vol. 83, No. 9, pp. 1351-1360.

Genetic Association between Alzheimer’s Disease Risk Variant of the PICALM and Auditory Event-Related Potentials in Aging

N. V. Ponomareva1,2,a*, T. V. Andreeva2,3, M. A. Protasova2, Yu. V. Filippova1, E. P. Kolesnikova1, V. F. Fokin1, S. N. Illarioshkin1, and E. I. Rogaev2,3,4,b*

1Research Center for Neurology, 125367 Moscow, Russia 2Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991 Moscow, Russia 3Lomonosov Moscow State University, Department of Biology, Center of Genetics and Genetic Technologies, 119991 Moscow, Russia 4Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, USA ae-mail: [email protected] be-mail: [email protected] Received May 21, 2018 Revision received June 26, 2018

Abstract—Aging and genetic predisposition are major risk factors in age-related neurodegenerative disorders. The most common neurodegenerative disorder is Alzheimer’s disease (AD). Genome-wide association studies (GWAS) have identi- fied statistically significant association of the PICALM rs3851179 polymorphism with AD. The PICALM G increases the risk of AD, while the A allele has a protective effect. We examined the association of the PICALM rs3851179 polymor- phism with parameters of the P3 component of auditory event-related potentials (ERPs) in 87 non-demented volunteers (age, 19-77 years) subdivided into two cohorts younger and older than 50 years of age. We found statistically significant asso- ciation between the AD risk variant PICALM GG and increase in the P3 latency in subjects over 50 years old. The age- dependent increase in the P3 latency was more pronounced in the PICALM GG carriers than in the carriers of the PICALM AA and PICALM AG genotypes. The observed PICALM-associated changes in the neurophysiological processes indicate a decline in the information processing speed with aging due, probably, to neuronal dysfunction and subclinical neurodegen- eration of the neuronal networks in the hippocampus and the frontal and parietal cortical areas. Such changes were less pro- nounced in the carriers of the PICALM gene A allele, which might explain the protective effect of this allele in the cognitive decline and AD development.

DOI: 10.1134/S0006297918090092

Keywords: PICALM genotype, neurodegeneration, aging, genetic predisposition, Alzheimer’s disease, event-related poten- tials, P300

Aging and genetic predisposition are the greatest Polymorphism of the apolipoprotein E gene (ApoE) known risk factors in the development of age-related neu- located on 19 is the most common AD risk rodegenerative disorders, the most common of which are factor. The ApoE ε4 allele markedly elevates the risk of Alzheimer’s disease (AD) and Parkinson’s disease (PD). AD; however, it is not necessary or sufficient for AD The development of AD, especially of the early- development [6, 7]. onset familial AD, is related to mutations in the Recently, a remarkable progress in identifying new encoding presenilin 1 (PSEN1) [1, 2], presenilin 2 genes with lower impact and penetrance but still associat- (PSEN2) [2-4], and amyloid precursor (APP) [5]. ed with increased risk of AD development, has been achieved by using genome-wide association studies Abbreviations: AD, Alzheimer’s disease; EEG, electroen- (GWAS). Thus, it was found that the PICALM rs3851179 cephalogram; ERPs, event-related potentials; LP, latency peri- polymorphism is associated with the AD development [8, od; PD, Parkinson’s disease. 9]. PICALM (chromosome 11q14) has been described as * To whom correspondence should be addressed. one of the six most common risk genes in the AlzGene

1075 1076 PONOMAREVA et al. susceptibility gene database (http://www.AlzGene.org). ly in AD [23, 26, 28, 30]. The amplitude of P3 decreases The PICALM allele G increases the risk of AD develop- in AD (the data on P3 amplitude in normal aging are con- ment, while the A allele decreases this risk [10, 11]. It was troversial) [28, 31]. found that epistatic and additive interaction between Several studies have demonstrated an association genes identified in GWAS (including PICALM and ApoE between the genetic risk factors for AD and the parame- genotypes) might be involved in AD development [12, 13]. ters of cognitive ERPs. Analysis of cognitive ERPs in a PICALM encodes phosphatidylinositol-binding small cohort of 30 elderly females including 10 carriers of clathrin assembly protein involved in clathrin-mediated the ApoE E4+ genotype found that the latency of the P3 endocytosis (CME) [14]. CME is a component of some component of auditory ERPs in the examined subjects metabolic pathways playing a crucial role in AD patho- increased, while the neuropsychological parameters of genesis, such as formation and clearance of β-amyloid memory were comparable between ApoE E4+ carriers and and tau protein clearance by autophagy [15-17]. non-carriers [32]. It was also shown that the P3 latency PICALM modulates neuronal trafficking, including the was increased in clinically asymptomatic relatives of AD transport of synaptic vesicle protein VAMP2 required for patients [33]. Similarly, elevated latency of the late com- the neurotransmitter release from presynaptic terminals ponents of visual ERPs was found in clinically asympto- [18]. It was found that PICALM expression depends on matic relatives of AD patients [34]. the PICALM rs3851179 polymorphism [19]. The impact of PICALM polymorphism on cognitive The PICALM rs3851179 polymorphism is associated ERPs in normal aging and neurodegenerative diseases with the hippocampus size and the entorhinal cortex remains unexplored. thickness in healthy individuals, patients with mild cogni- Our study was aimed at investigating the association tive impairment (MCI), and AD patients [20, 21]. between the PICALM rs3851179 polymorphism and the Earlier, we investigated the functional role of the P3 component of auditory ERPs and how it might be PICALM rs3851179 polymorphism using the resting-state affected by aging. quantitative electroencephalography (qEEG) and revealed association between the studied PICALM polymorphism and age-related changes in the β EEG activity [22]. MATERIALS AND METHODS Other sensitive tools that can be used for assessing functional changes in the brain in normal and pathologi- Subjects. A total of 87 non-demented volunteers, 43 cal aging are cognitive components of event-related males and 44 females, aged 19-77 (mean age, 48.0 ± 1.7 potentials (ERPs) that reflect brain activity directly years) were examined after undergoing neurological and involved in decision making, memory, and attention. psychometric examination. The exclusion criteria were as ERPs generation is a result of summation of excitatory follows: neurological or mental disorders including cardio- and inhibitory postsynaptic potentials (EPSPs and IPSPs, vascular diseases, psychiatric diseases, epilepsy, as well as respectively) mainly in the pyramidal neurons of the psychiatric or neurological disorders in subject’s history. frontal, parietal, and temporal cortical structures and the All subjects were divided into groups according to the hippocampus [23-27]. Cognitive ERPs have been used to PICALM rs3851179 polymorphism. The PICALM AA&AG examine neurophysiological mechanisms underlying cog- group consisted of homozygous PICALM AA or heterozy- nitive disorders in aging and neurodegenerative diseases gous PICALM AG carriers; the PICALM GG group includ- (e.g., MCI, AD, and PD) [26, 28, 29]. This method sur- ed homozygous PICALM GG carriers. Each group was fur- passes functional magnetic resonance imaging in tempo- ther subdivided into subgroups with subjects younger and ral resolution (but not in spatial resolution). older than 50 years of age. The most studied and informative parameter is the All subjects were genotyped for ApoE. ERPs positive P3 component (P300) elicited ~300 ms Cognitive auditory ERPs recordings. Cognitive audi- after the onset of a rare stimulus in the cognitive task tory ERPs were recorded with a computerized Neuro- involving identification of rare “target” stimuli within a KM system (Statokin, Russia) using the monopolar series of frequently presented “standard” stimuli (the so- recording in the parietal (P3, P4), frontal (F3, F4) and called oddball paradigm). central (Cz) areas according to the International 10-20 Multiple studies (including intracranial ones) System. Auditory ERPs were recorded according to a demonstrated that the P3 component is mainly elicited by standard auditory discrimination protocol using target the neuronal networks of the frontal, temporal, and pari- and non-target stimuli (oddball paradigm). The target etal cortical areas and the hippocampus, the frontal cortex stimuli were recognized as 2000-Hz clicks among fre- being responsible predominantly for attention, while tem- quent 1000-Hz standard stimuli. The subject was required poral and parietal areas – for memory functions [26, 27]. to distinguish between the two tones by mentally counting The P3 latency gradually increases with normal the target tones and not responding to the standard. aging, and it is significantly elevated in neurodegenerative Binaural stimuli were applied for 50 ms; the stimulus diseases accompanied by cognitive impairment, especial- intensity was 80-90 dB (in accordance with the auditory

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Table 1. Demographic characteristics of healthy subjects with different PICALM genotypes

Subjects under 50 years of age Subjects over 50 years of age All subjects, aged 19-77

PICALM AA&AG PICALM GG PICALM AA&AG PICALM GG PICALM AA&AG PICALM GG

Number 30 12 25 20 55 32 of subjects

Age, years 34.3 ± 1.5 35.7 ± 3.4 61.1 ± 1.6 59.5 ± 1.7 46.5 ± 2.1 50.5 ± 2.6

Gender 17/13 4/8 13/12 9/11 30/25 13/19 (males/females)

Note: Data are presented as mean ± S.E. threshold); the frequency was 1 Hz. The stimuli were The distribution of polymorphism variants was test- applied in a pseudo-random order at a 7 : 3 target/non- ed for its correspondence to the Hardy–Weinberg equa- target ratio. Sweeps to targets were visually inspected for tion by using the χ2-test. artefacts before being accepted into the average. The averaging number for target stimuli was 40-46. Control experiments demonstrated that the averaging number RESULTS within the studied range did not influence the parameters of cognitive ERPs. The pre-stimulus interval was 100 ms; Demographic parameters of the subjects enrolled in the epoch length was 600 ms. We measured the N2–P3 the study are shown in Table 1. No significant age and sex interpeak amplitude (µV). The P3 latency was defined differences between the PICALM GG and PICALM relative to stimulus onset. AA&AG carriers were found in the cohorts younger and Genotyping. DNA was isolated from peripheral older than 50 years of age, as well as in the total sample blood mononuclear cells by a standard phenol-chloro- (p > 0.05). The frequencies of the G and A were form extraction method with a Qiagen kit (Qiagen, The 60.3 and 39.7%, respectively. The observed genotype dis- Netherlands). PICALM genotyping was performed by tribution did not differ from the one expected according PCR followed by restriction fragment length polymor- to the Hardy–Weinberg equation (χ2 = 0.02; p > 0.99). phism (RFLP) analysis as described in [22]. ApoE geno- Statistical analysis revealed the dependence of the P3 typing was performed by PCR as described in [12]. latency on the PICALM Genotype (F[1.81] = 4.1; p < Statistical analysis. The differences in the P3 latency 0.05). As demonstrated by post-hoc comparison, the P3 and amplitude of cognitive ERPs were assessed by latency in the PICALM GG group was longer than in the ANOVA using repeated measurements in the general lin- PICALM AA&AG group in the frontal (p < 0.01), parietal ear model (GLM) with the (i) between-subject factors (p < 0.02), and central (p < 0.02) brain areas (Table 2). Genotype (PICALM AA&AG vs PICALM GG) and Age The P3 latency also depended on Age (F[1.81] = (younger vs older than 50 years of age) and (ii) within- 13.1; p < 0.001) (Fig. 1). Thus, in individuals over 50 years subject factors Recording Area (frontal F, parietal P, and old, the P3 latency was greater in the PICALM GG group central C) and Asymmetry (right and left hemispheres). than in the PICALM AA&AG group (post-hoc comparison) PICALM AA and PICALM AG genotype carriers were in the frontal (p = 0.02), parietal (p = 0.03), and vertex grouped together, because the PICALM AA group con- (p = 0.05) areas. However, in individuals younger than 50 tained a relatively small number of subjects (14 individu- years of age, this difference was not significant (Fig. 1). als), and ANOVA did not reveal significant differences between the ERP parameters in the PICALM AA and Table 2. P3 latency (ms) in healthy subjects with different PICALM AG carriers. The data were checked for spheric- PICALM genotypes ity because of the introduction of within-subject factors into the model. In case the sphericity was violated, the Area PICALM AA&AG PICALM GG Greenhouse–Geisser correction was applied. The ApoE F 314.2 ± 3.7 336.6 ± 5.6 genotype was included as a fixed factor into the GLM for statistical processing of the results. P 319.4 ± 4.1 336.2 ± 6.2 The Duncan’s test was used in post-hoc comparisons C 317.4 ± 3.9 333.3 ± 5.0 at p < 0.05. The dependence of P3 amplitude and latency on age Notes: Data are presented as mean ± S.E; F, frontal area; P, parietal was estimated using Pearson correlation coefficient. area; C, central area.

BIOCHEMISTRY (Moscow) Vol. 83 No. 9 2018 1078 PONOMAREVA et al. , ms LP

Fig. 1. Latency (latent period, LP) of the P3 component of auditory ERPs in healthy subjects under (1) and over (2) 50 years of age carrying different PICALM genotypes. F, P and C are frontal, parietal and central brain areas, respectively; * p < 0.05, significant difference between PICALM GG and PICALM AA&AG genotype carriers; # p < 0.05, significant difference between subjects younger and older than 50 years of age. Amplitude, µV

Fig. 2. Amplitude of the P3 component of auditory ERPs in healthy subjects under (1) and over (2) 50 years of age carrying different PICALM genotypes.

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r = 0.3; p = 0.03 r = 0.59; p < 0.001 , ms LP

Age, years

Fig. 3. Correlation between age and P3 latency (LP) in the vertex (Cz) area in healthy subjects with different PICALM genotypes. Dashed lines, 95% confidence interval.

The P3 latency was longer in PICALM GG carriers the examined areas. No significant correlation between older vs. younger than 50 years of age in the frontal (p = the P3 latency and age was found in the parietal area in 0.02), parietal (p < 0.001) and central (p = 0.006) brain the PICALM AA&AG group, while in the frontal and cen- areas. The PICALM AA&AG group also showed an tral areas, this correlation was less significant than in increase in the P3 latency with age, although the differ- PICALM GG group (Table 3 and Fig. 3). ence between the subjects younger vs. older than 50 years was not significant (Fig. 1). The ANOVA did not reveal any effect of between-sub- DISCUSSION ject factors (Genotype and Age) on P3 amplitude (Fig. 2). No interaction between the PICALM Genotype and In this study, we revealed an association between the the within-subject factors was observed. PICALM rs3851179 polymorphism and the latency of the Correlation analysis revealed that the P3 latency in P3 component of auditory ERPs in adult non-demented PICALM GG carriers significantly increased with age in all volunteers. Significantly increased P3 latency in the car-

Table 3. Correlation between age and P3 latency in healthy subjects with different PICALM genotypes

PICALM GG PICALM AA&AG Area of recording r p r p

F4 0.46 0.008 0.27 0.04 F3 0.40 0.02 0.16 >0.05 P4 0.52 0.002 0.21 >0.05 P3 0.45 0.01 0.23 >0.05 Cz 0.59 <0.001 0.30 0.03

BIOCHEMISTRY (Moscow) Vol. 83 No. 9 2018 1080 PONOMAREVA et al. riers of AD risk PICALM GG vs. the carriers of the protec- tors; however, the significance of such factors in the mod- tive PICALM AA & PICALM AG genotypes was observed ulation of cognitive ERPs requires further investigation. in subjects over 50 years old in all examined brain regions (frontal, parietal, and central areas). The correlation Overall, our results confirm that investigation of the between age and increase in the P3 latency was more pro- role of genetic factors in the development of functional nounced in the carriers of the AD risk PICALM GG geno- alterations in aging brain is relevant to unveil the mecha- type vs. the PICALM AA & PICALM AG carriers. nisms underlying such alterations. This approach could More pronounced increase in the P3 latency in the potentially allow to develop personalized strategies of carriers of the PICALM GG AD risk genotype indicates that treatment and efficient prevention of neurodegenerative information processing is slowed down in the hippocam- disorders [2, 7, 40-44]. pus and parietal and frontal cortical structures of these In conclusion, we found that the latency of P3 (P300) subjects due probably to early neurodegeneration resulting component of auditory ERPs was increased in healthy car- in the reduced size of the hippocampus and decreased riers of the AD risk PICALM GG genotype vs. carriers of the thickness of the entorhinal cortex [26, 27]. These changes PICALM AA and PICALM AG genotypes, with the effect were less pronounced in the carriers of the protective A being more pronounced in subjects older than 50 years of allele. Our results corroborate the data published by Biffi et age. The processing of information in the PICALM GG car- al. [20] on the association between the PICALM polymor- riers progressively slows down with aging due probably to phisms and reduced size of the hippocampus and neuronal dysfunction and subclinical neurodegeneration in decreased thickness of the entorhinal cortex. An increase the neuronal networks of the frontal and parietal cortical in the P3 latency underlies memory impairments and structures and the hippocampus. In the PICALM allele A attention deficit and correlates with neuropsychological carriers, these changes were less pronounced, which may measures of these cognitive functions [23-26, 31]. explain protective effects of this allele on the rate of cogni- The impact of the PICALM genotype on the neuronal tive decline in aging and, probably, in AD development. dysfunction and neurodegeneration manifested as altered cognitive ERPs can be caused by the effect of PICALM genotype on the generation and clearance of β-amyloid, Funding as well as clearance of tau protein [14-17]. Acording to the current dominant model of AD pathogenesis, generation This study was supported by the Russian Science and accumulation of neurotoxic β-amyloid in the brain is Foundation (project no. 14-44-00077; genotyping) and a pivotal pathogenic event that triggers release and intra- the National Institutes of Health, USA (grant cellular accumulation of hyperphosphorylated tau pro- R01AG054712 to E.R.; statistical analysis). tein, impaired mitochondrial function, excitotoxicity, oxidative stress, and inflammatory reactions eventually resulting in neurodegeneration [35]. Conflict of Interests PICALM-linked processes are also involved in neu- rotransmission [18]. Previously, we found that the The authors declare no financial or other conflicts of PICALM GG genotype is associated with an increase in the interest. EEG beta activity in aging [22]. The EEG β activity is related to glutamate-mediated neurotransmission. Glutamate-associated excitotoxicity may promote neu- Ethical Committee Approval rodegeneration in carriers of the PICALM GG genotype. The PICALM rs3851179 polymorphism was also All procedures with volunteers were conducted in shown to be associated with PD development [36], accordance with the ethical standards of the National although some studies failed to find this association [37]. Committee for Research Ethics and the Declaration of The most damaged cells in PD are dopaminergic neurons Helsinki 1964, as well as its subsequent revisions and of substantia nigra. α-Synuclein plays a crucial role in PD comparable ethical standards. pathogenesis, affects clathrin-mediated endocytosis of All subjects provided a written informed consent to NMDA receptors and influences NMDA-dependent participate in the study performed in accordance with the death of dopaminergic neurons [38]. protocol approved by the Ethics Committee at the The latency of cognitive ERPs is increased in both Research Center of Neurology and Vavilov Institute of non-demented and demented PD patients, but this General Genetics, Russian Academy of Sciences. increase is more pronounced in the demented PD patents [39]. PD is also characterized by cognitive impairments, REFERENCES although less pronounced than in AD [40]. It cannot be ruled out that age-associated changes in cognitive ERPs 1. 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